ABSTRACT The ultimate goal of this project is to address the unmet clinical need in breast cancer screening for women with high breast density. This population (BI-RADS density grades C and D) accounts for nearly half of women. The high breast density reduces mammography sensitivity to as low as 62%, and it is also associated with a two-fold higher risk of breast cancer (American College of Obstetricians and Gynecologists, Management of Women With Dense Breasts Diagnosed by Mammography, 2016). While 30 states have now passed breast density notification laws, there is no promising modality for large-scale screening of patients with dense breasts. For instance, the breast ultrasound (US) is operator-dependent, and has limited sensitivity and a high false positive rate; while dynamic contrast-enhanced (DCE) breast magnetic resonance imaging (MRI) is limited by its high cost, required injection of gadolinium contrast, and limited availability. To address this issue, this project will develop a three- dimensional (3D) breast screening system with both photoacoustic (PA) and US imaging capabilities. The proposal is capitalized on the team?s recent advances in the double-scan PA technology, which utilized two linear transducer arrays and two linear optical fiber bundles to image a slightly compressed breast from both the cranial and caudal (CC) sides. With a novel co-planar optical illumination and acoustic detection design, the prototype system successfully imaged through a 7-cm-thick compressed breast. This depth has never been achieved by any other PA breast imaging systems. The CC-view detection also presents images in a form that is familiar to radiologists. In addition, the system is portable and images the patient in a standing pose, both of these features will significantly facilitate clinical workflow. This R01 project will further advance the dual-scan system to achieve better breast coverage, higher spatial resolution, better US capability, and multi-parametric quantification of breast tissue. To ensure successful implementation of the project, the team possesses multidisciplinary expertise in photoacoustics, ultrasound, computational informatics, biostatistics, as well as breast oncology and radiology. The project has also secured support from the Buffalo?s two busiest breast imaging centers ? Roswell Park Cancer Institute and Windsong Radiology Group. The specific aims of the project are as follows: Aim 1. Develop a compact double-scan photoacoustic and ultrasonic breast imaging system. Aim 2. Develop photoacoustic and ultrasound image acquisition and processing algorithms. Aim 3. Investigate photoacoustic and ultrasonic features of breast malignancy.